NO178497B - Process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process - Google Patents
Process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process Download PDFInfo
- Publication number
- NO178497B NO178497B NO913686A NO913686A NO178497B NO 178497 B NO178497 B NO 178497B NO 913686 A NO913686 A NO 913686A NO 913686 A NO913686 A NO 913686A NO 178497 B NO178497 B NO 178497B
- Authority
- NO
- Norway
- Prior art keywords
- imidazole
- amino
- carboxamide
- thiocarbamoyl
- substituted
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 18
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000000543 intermediate Chemical class 0.000 title claims description 4
- 150000003839 salts Chemical class 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- -1 peroxy compound Chemical class 0.000 claims description 10
- 229910001385 heavy metal Inorganic materials 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- QMYVMPRLRSVZBL-UHFFFAOYSA-N 4-(carbamothioylamino)-1h-imidazole-5-carboxamide Chemical class NC(=S)NC=1N=CNC=1C(N)=O QMYVMPRLRSVZBL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052721 tungsten Inorganic materials 0.000 claims description 3
- 239000010937 tungsten Substances 0.000 claims description 3
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 229910052745 lead Inorganic materials 0.000 claims description 2
- 229910052753 mercury Inorganic materials 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 229910001868 water Inorganic materials 0.000 description 27
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 4
- 229960004150 aciclovir Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- SCOKPTHVGOEBIW-UHFFFAOYSA-N 2-[(5-amino-4-carbamoylimidazol-1-yl)methoxy]ethyl acetate Chemical compound CC(=O)OCCOCN1C=NC(C(N)=O)=C1N SCOKPTHVGOEBIW-UHFFFAOYSA-N 0.000 description 3
- NSXZKVSKOIMUKN-UHFFFAOYSA-N 5-(carbamothioylamino)-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1NC(N)=S NSXZKVSKOIMUKN-UHFFFAOYSA-N 0.000 description 3
- QTKYYXIZORIEEI-UHFFFAOYSA-N 5-(carbamothioylamino)-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1NC(N)=S QTKYYXIZORIEEI-UHFFFAOYSA-N 0.000 description 3
- APLNCUAOMQJOIZ-UHFFFAOYSA-N 5-(carbamothioylamino)-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1NC(N)=S APLNCUAOMQJOIZ-UHFFFAOYSA-N 0.000 description 3
- DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical class NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 description 3
- UUWJNBOCAPUTBK-UHFFFAOYSA-N 9-methylguanine Chemical compound N1=C(N)N=C2N(C)C=NC2=C1O UUWJNBOCAPUTBK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229910000365 copper sulfate Inorganic materials 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- KZYOKOLLHMHOLR-UHFFFAOYSA-N 1-benzyl-5-(carbamothioylamino)imidazole-4-carboxamide Chemical compound NC(=S)NC1=C(C(N)=O)N=CN1CC1=CC=CC=C1 KZYOKOLLHMHOLR-UHFFFAOYSA-N 0.000 description 2
- SMHBTBYHDWNJEG-UHFFFAOYSA-N 2-amino-9-benzyl-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1CC1=CC=CC=C1 SMHBTBYHDWNJEG-UHFFFAOYSA-N 0.000 description 2
- WDOYBEPLTCFIRQ-UHFFFAOYSA-N 2-amino-9-ethyl-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CC)C=N2 WDOYBEPLTCFIRQ-UHFFFAOYSA-N 0.000 description 2
- OSFDSLRVYKUBOP-UHFFFAOYSA-N 2-amino-9-propyl-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CCC)C=N2 OSFDSLRVYKUBOP-UHFFFAOYSA-N 0.000 description 2
- QURCXIIQSAIIAR-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-benzylimidazole-4-carboxamide Chemical compound C=1C=CC=CC=1C(=O)NC(=S)NC1=C(C(=O)N)N=CN1CC1=CC=CC=C1 QURCXIIQSAIIAR-UHFFFAOYSA-N 0.000 description 2
- AIVZNYNMAVQYDV-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 AIVZNYNMAVQYDV-UHFFFAOYSA-N 0.000 description 2
- BIPYIUKMNFPYHS-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 BIPYIUKMNFPYHS-UHFFFAOYSA-N 0.000 description 2
- ALUGLKCVKRCHSR-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 ALUGLKCVKRCHSR-UHFFFAOYSA-N 0.000 description 2
- YBGIFRCRSMJOMZ-UHFFFAOYSA-N 5-(carbamothioylamino)-1-(2-hydroxyethoxymethyl)imidazole-4-carboxamide Chemical compound NC(=S)NC1=C(C(N)=O)N=CN1COCCO YBGIFRCRSMJOMZ-UHFFFAOYSA-N 0.000 description 2
- DRPRDPXASLIYCT-UUOKFMHZSA-N 5-(carbamothioylamino)-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]imidazole-4-carboxamide Chemical compound NC(=S)NC1=C(C(N)=O)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DRPRDPXASLIYCT-UUOKFMHZSA-N 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229940029575 guanosine Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- IMLPOIKFZQDSIW-UHFFFAOYSA-N 2-amino-9-[hydroxy(1-hydroxypropan-2-yloxy)methyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(C(O)OC(CO)C)C=N2 IMLPOIKFZQDSIW-UHFFFAOYSA-N 0.000 description 1
- QFCCFUBHVTZGJS-UHFFFAOYSA-N 5-amino-1-[hydroxy(1-hydroxypropan-2-yloxy)methyl]imidazole-4-carboxamide Chemical compound OCC(C)OC(O)N1C=NC(C(N)=O)=C1N QFCCFUBHVTZGJS-UHFFFAOYSA-N 0.000 description 1
- JAODJMVGFQELNO-UHFFFAOYSA-N 5-amino-1-benzylimidazole-4-carboxamide Chemical compound NC1=C(C(=O)N)N=CN1CC1=CC=CC=C1 JAODJMVGFQELNO-UHFFFAOYSA-N 0.000 description 1
- WMRBKFPTMPNISL-UHFFFAOYSA-N 5-amino-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1N WMRBKFPTMPNISL-UHFFFAOYSA-N 0.000 description 1
- UZHKJZZQGXMAKP-UHFFFAOYSA-N 5-amino-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1N UZHKJZZQGXMAKP-UHFFFAOYSA-N 0.000 description 1
- LVONFJCKVYNYTJ-UHFFFAOYSA-N 5-amino-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1N LVONFJCKVYNYTJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- BWFPGXWASODCHM-UHFFFAOYSA-N copper monosulfide Chemical compound [Cu]=S BWFPGXWASODCHM-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/052—Imidazole radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Teknisk område Technical area
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av 9-substituerte guaninderivater med den generelle formel I The present invention relates to a method for the production of 9-substituted guanine derivatives with the general formula I
hvor R er C^-C^-alkyl som eventuelt er substituert med én eller flere hydroksygrupper, eller R er benzyl, ribosyl, 2'-deoksyribosyl eller (CH^-OR1, hvor n er 1 eller 2, og R<1> er CH2CH2OH eller where R is C^-C^-alkyl optionally substituted with one or more hydroxy groups, or R is benzyl, ribosyl, 2'-deoxyribosyl or (CH^-OR1, where n is 1 or 2, and R<1> is CH2CH2OH or
eller salter derav. or salts thereof.
Forbindelser av denne type er terapeutisk aktive forbindelser som har en antiviral aktivitet, eller er mellomprodukter for fremstillingen av forbindelser av interesse innen genteknologi. Compounds of this type are therapeutically active compounds that have an antiviral activity, or are intermediates for the production of compounds of interest in genetic engineering.
Teknikkens stand State of the art
Det er kjent (J. Org. Chem., 51, s. 1277-1282 (1986)) at guanosin kan fremstilles fra 4-karboksamid-5-amino-l-ribofuranosyl-imidazol ved en fremgangsmåte i tre trinn som omfat-ter kondensasjon med karbodiimidderivater, ringslutning med PdO til stede og behandling med NH4OH. Denne fremgangsmåten er ikke attraktiv ettersom den krever bruk av den toksiske forbindelse fosgen for å fremstille karbodiimidderivatene, og fordi ringslutningen og den etterfølgende behandling med NH4OH tar svært lang tid. It is known (J. Org. Chem., 51, pp. 1277-1282 (1986)) that guanosine can be prepared from 4-carboxamide-5-amino-1-ribofuranosyl-imidazole by a three-step process comprising condensation with carbodiimide derivs., ring closure with PdO present and treatment with NH4OH. This process is not attractive because it requires the use of the toxic compound phosgene to prepare the carbodiimide derivatives, and because the cyclization and subsequent treatment with NH 4 OH takes a very long time.
Det er også kjent at forbindelsen med formel I, hvor R er H, kan fremstilles ved en fremgangsmåte hvor forbindelsen med formel II It is also known that the compound of formula I, where R is H, can be prepared by a process where the compound of formula II
først metyleres for dannelse av den tilsvarende tiometylfor-bindelse som så ringsluttes i alkalisk medium (A. Yamazaki, Nucl. Acids. Res., 3, 1976, s. 251-259). Denne fremgangsmåten har den ulempe at det toksiske og dårlig svellende metyl-merkaptan dannes som et biprodukt, og dessuten er utbyttet dårlig. Det er rapportert i artikkelen at ringslutning av forbindelsen II under anvendelse av tungmetallsaltet HgO ikke er mulig. is first methylated to form the corresponding thiomethyl compound which is then cyclized in an alkaline medium (A. Yamazaki, Nucl. Acids. Res., 3, 1976, pp. 251-259). This method has the disadvantage that the toxic and poorly swelling methyl mercaptan is formed as a by-product, and furthermore the yield is poor. It is reported in the article that cyclization of compound II using the heavy metal salt HgO is not possible.
Beskrivelse av oppfinnelsen Description of the invention
Overraskende har vi imidlertid funnet at det er mulig å utføre ringslutning av I^-substituerte derivater av forbindelser med formel II uten først å metylere, og anvende et tungmetallsalt i vandig, alkalisk medium eller anvende per-oksyforbindelser. Surprisingly, however, we have found that it is possible to carry out cyclization of I^-substituted derivatives of compounds of formula II without first methylating, and using a heavy metal salt in an aqueous, alkaline medium or using peroxy compounds.
Fremgangsmåten ifølge oppfinnelsen er kjennetegnet ved at et 1-substituert 5-(tiokarbamoyl)amino-lH-imidazol-4-karboksamid med den generelle formel III The method according to the invention is characterized by the fact that a 1-substituted 5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide of the general formula III
hvor R har den samme betydning som i formel I, ringsluttes where R has the same meaning as in formula I, the ring is closed
a) ved behandling med et tungmetallsalt fra gruppen Cu-, Ag-, Pb- og Hg-salter i et vandig, alkalisk medium inneholdende minst fire ekvivalenter OH"-ioner ved en temperatur fra 0 °C til reflukstemperaturen, eller b) ved behandling med en peroksyforbindelse i et vandig, alkalisk medium ved en temperatur på 0-30 °C i nærvær av wolframioner som katalysator, a) by treatment with a heavy metal salt from the group of Cu, Ag, Pb and Hg salts in an aqueous, alkaline medium containing at least four equivalents of OH" ions at a temperature from 0 °C to the reflux temperature, or b) by treatment with a peroxy compound in an aqueous, alkaline medium at a temperature of 0-30 °C in the presence of tungsten ions as a catalyst,
hvoretter I isoleres ved behandling med syre og, om ønsket, omdannes til et salt. after which I is isolated by treatment with acid and, if desired, converted to a salt.
Utgangsforbindelsene med formel III The starting compounds of formula III
hvor R er C^-C^-alkyl, benzyl, p-D-ribofuranosyl eller (CH2)n-OR<1>, hvor n er 1 eller 2, og R<1> er CH2CH2OH eller eller salter derav, er nye forbindelser, og oppfinnelsen om-fatter derfor videre disse forbindelsene som mellomprodukter for fremstillingen av 9-substituerte guaninderivater med formel I. Utgangsmaterialene med formel III kan fremstilles ved omsetning av 1-substituerte 5-amino-lH-imidazol-4-karboks-amider med formel IV where R is C^-C^-alkyl, benzyl, p-D-ribofuranosyl or (CH2)n-OR<1>, where n is 1 or 2, and R<1> is CH2CH2OH or or salts thereof, are new compounds, and the invention therefore further includes these compounds as intermediates for the preparation of 9-substituted guanine derivatives of formula I. The starting materials of formula III can be prepared by reaction of 1-substituted 5-amino-1H-imidazole-4-carboxamides of formula IV
hvor R har den samme betydning som i formel III og hvor eventuelle hydroksylgrupper i R kan være acylerte, med acyltio-cyanat og etterfølgende hydrolyse for å fjerne N-acylgruppen og eventuelle andre acylgrupper. where R has the same meaning as in formula III and where any hydroxyl groups in R can be acylated, with acyl thiocyanate and subsequent hydrolysis to remove the N-acyl group and any other acyl groups.
Forbindelsene med formel IV kan fremstilles ved alkylering av den kjente forbindelse 5-amino-lH-imidazol-4-karboksamid på kjent måte. The compounds of formula IV can be prepared by alkylating the known compound 5-amino-1H-imidazole-4-carboxamide in a known manner.
Beste måte å utføre oppfinnelsen på Best way to carry out the invention
Fremgangsmåten ifølge oppfinnelsen i variant a) ut-føres fortrinnsvis under anvendelse av et kobbersalt som tungmetallsaltet. Herved fås et høyt utbytte med et billig reagens. The method according to the invention in variant a) is preferably carried out using a copper salt as the heavy metal salt. This results in a high yield with a cheap reagent.
Fremgangsmåten i variant a) utføres dessuten fordel-aktig på den måte at det vandige, alkaliske medium tilveie-bringes med et alkalimetallhydroksid, fortrinnsvis natrium-eller kaliumhydroksid. The method in variant a) is also advantageously carried out in such a way that the aqueous, alkaline medium is provided with an alkali metal hydroxide, preferably sodium or potassium hydroxide.
Fremgangsmåten ifølge oppfinnelsen i variant b) ut-føres fortrinnsvis under anvendelse av hydrogenperoksid som peroksyforbindelsen. The method according to the invention in variant b) is preferably carried out using hydrogen peroxide as the peroxy compound.
Fremstilling av utgangsmaterialer Production of starting materials
Fremstilling av 5-( N'- benzovltiokarbamovl) amino- 1- metyl- 1H-imidazol- 4- karboksamid Preparation of 5-(N'-benzoylthiocarbamoyl)amino-1-methyl-1H-imidazole-4-carboxamide
5-amino-l-metyl-lH-imidazol-4-karboksamid (6,5 g, 5-amino-1-methyl-1H-imidazole-4-carboxamide (6.5 g,
45 mM) og benzoylisotiocyanat (7,7 g, 47 mM) ble kokt under tilbakeløpskjøling i aceton (90 ml) i 4 timer under N2. Etter avkjøling på et isbad ble det dannede produkt frafiltrert, vasket med aceton og tørket- Herved ble det isolert 13,0 g (95 %) av tittelforbindelsen som et hvitt pulver, sm.p. 194-196 °C. 45 mM) and benzoyl isothiocyanate (7.7 g, 47 mM) were refluxed in acetone (90 mL) for 4 h under N 2 . After cooling in an ice bath, the product formed was filtered off, washed with acetone and dried. This isolated 13.0 g (95%) of the title compound as a white powder, m.p. 194-196 °C.
5-( N'- benzoyltiokarbamoyl) amino- l- etyl- lH- imidazol- 4- karboksamid ble fremstilt på en lignende måte fra 5-amino-l-etyl-lH-imidazol-4-karboksamid, sm.p. 178-180 °C. 5-(N'-benzoylthiocarbamoyl)amino-1-ethyl-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-amino-1-ethyl-1H-imidazole-4-carboxamide, m.p. 178-180 °C.
5-( N'- benzoyltiokarbamoyl) amino- l-( 1- propyl)- lH- imidazol- 4-karboksamid ble fremstilt på en lignende måte fra 5-amino-l-(1-propyl)-lH-imidazol-4-karboksamid, sm.p. 163-164 "C. 5-(N'-benzoylthiocarbamoyl)amino-1-(1-propyl)-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-amino-1-(1-propyl)-1H-imidazole-4- carboxamide, m.p. 163-164 "C.
5-( N'- benzoyltiokarbamoyl) amino- l- benzyl- lH- imidazol- 4- karboksamid ble fremstilt på en lignende måte fra 5-amino-l-benzyl-lH-imidazol-4-karboksamid, sm.p. 181-182,5°C. 5-(N'-benzoylthiocarbamoyl)amino-1-benzyl-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-amino-1-benzyl-1H-imidazole-4-carboxamide, m.p. 181-182.5°C.
1- f( 2- hydroksyetoksy) metyll- 5-( tiokarbamoyl) amino- lH- imidazol-4- karboksamid 1-f(2-hydroxyethoxy)methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide
5-amino-l-[[2-(acetyloksy)etoksy]metyl]-lH-imidazol-4-karboksamid (44,0 g, 182 mM) og benzoylisotiocyanat (29,7 g, 182 mM) ble kokt under tilbakeløpskjøling i aceton (430 ml) i 1 time. Til den resulterende oppløsning ble det tilsatt metanol (430 ml) og kaliumkarbonat (14,9 g, 108 mM) oppløst i vann (45 ml), hvoretter blandingen ble kokt under tilbakeløps-kjøling i 4 timer. Etter avkjøling til værelsestemperatur ble eddiksyre tilsatt til en pH-verdi på 8. Det dannede produkt ble frafiltrert ved 0 °C, vasket og tørket. Herved ble det isolert 39,2 g (83 %) av tittelforbindelsen som et hvitt pulver, sm.p. 181-182 °C (dek.). En prøve utkrystallisert fra vann hadde sm.p. 182-183 °C (dek.).13C-NMR (DMS0-d6) 6 ppm: 183,9; 163,7; 134,9; 129,3; 127,9; 74,0; 70,4; 59,7. 5-Amino-1-[[2-(acetyloxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (44.0 g, 182 mM) and benzoyl isothiocyanate (29.7 g, 182 mM) were refluxed in acetone (430 ml) for 1 hour. To the resulting solution was added methanol (430 mL) and potassium carbonate (14.9 g, 108 mM) dissolved in water (45 mL), after which the mixture was refluxed for 4 hours. After cooling to room temperature, acetic acid was added to a pH value of 8. The product formed was filtered off at 0 °C, washed and dried. In this way, 39.2 g (83%) of the title compound was isolated as a white powder, m.p. 181-182 °C (dec.). A sample crystallized from water had m.p. 182-183 °C (dec.). 13 C-NMR (DMS0-d6) 6 ppm: 183.9; 163.7; 134.9; 129.3; 127.9; 74.0; 70.4; 59.7.
Beregnet for C8H13N503S: Calculated for C8H13N503S:
C 37,06 %, H 5,05 %, N 27,01 %, S 12,37 % Funnet: C 36,92 %, H 5,07 %, N 27,30 %, S 12,28 %. C 37.06%, H 5.05%, N 27.01%, S 12.37% Found: C 36.92%, H 5.07%, N 27.30%, S 12.28%.
1- r 1, 3- dihydroksy-( 2- propyloksy) metyl]- 5-( tiokarbamovl) amino-lH- imidazol- 4- karboksamid ble fremstilt på en lignende måte fra 5-amino-[1,3-dihydroksy-(2-propyloksy)metyl]-lH-imidazol-4-karbbksamid, sm.p. 185 °C (dek.).13C-NMR (DMSO-d6) 6 ppm: 183,8; 163,9; 134,8; 129,2; 127,9; 80,2; 73,5; 60,7. 1-r1,3-dihydroxy-(2-propyloxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-amino-[1,3-dihydroxy-( 2-propyloxy)methyl]-1H-imidazole-4-carboxamide, m.p. 185 °C (dec.). 13 C-NMR (DMSO-d6) 6 ppm: 183.8; 163.9; 134.8; 129.2; 127.9; 80.2; 73.5; 60.7.
Beregnet for C9H15N504S: Calculated for C9H15N504S:
C 37,36 %, H 5,23 %, N 24,21 %, S 11,08 % Funnet: C 37,34 %, H 5,16 %, N 23,81 %, S 10,76 %. C 37.36%, H 5.23%, N 24.21%, S 11.08% Found: C 37.34%, H 5.16%, N 23.81%, S 10.76%.
1- f( 2- hydroksyetoksy) metyl]- 5-( tiokarbamovl) amino- lH- imidazol-4- karboksamid 1- f(2-hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide
Benzoylklorid (5,9 g, 42 mM) ble tilsatt dråpevis under N2 til en oppløsning av ammoniumtiocyanat (3,2 g, 42 mM) i aceton (80 ml) ved 25 °C i løpet av 5 min. Etter koking under tilbakeløpskjøling i 15 min ble det avkjølt til 20 °C, og det dannede ammoniumklorid ble frafiltrert og vasket med aceton (20 ml). Benzoyl chloride (5.9 g, 42 mM) was added dropwise under N 2 to a solution of ammonium thiocyanate (3.2 g, 42 mM) in acetone (80 mL) at 25 °C over 5 min. After boiling under reflux for 15 min, it was cooled to 20 °C, and the ammonium chloride formed was filtered off and washed with acetone (20 ml).
Til filtratet ble det tilsatt 5-amino-l-[[2-(acetyl-oksy)etoksy]metyl]-lH-imidazol-4-karboksamid (9,7 g, 40 mM). Blandingen ble kokt under tilbakeløpskjøling under N2 i 90 min. Så ble metanol (80 ml) og kaliumkarbonat (5,8 g, 42 mM) opp-løst i vann (12 ml) tilsatt, og blandingen ble kokt under til-bakeløpskjøling i 8 timer under N2. Vann (70 ml) ble tilsatt til hydrolyseblandingen, og den ble behandlet med aktivkull ved 25 °C. Oppløsningen ble så inndampet til ca. 70 ml og pH-verdien regulert til 7,0 med eddiksyre. Etter avkjøling til 5 °C ble det resulterende produkt frafiltrert, vasket med vann og tørket. Herved ble det isolert 8,0 g (77 %) av tittelforbindelsen som et hvitt pulver, sm.p. 178-180 °C (dek.). HPLC indikerte >96 % renhet. To the filtrate was added 5-amino-1-[[2-(acetyl-oxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (9.7 g, 40 mM). The mixture was refluxed under N2 for 90 min. Then methanol (80 mL) and potassium carbonate (5.8 g, 42 mM) dissolved in water (12 mL) were added and the mixture was refluxed for 8 h under N 2 . Water (70 ml) was added to the hydrolysis mixture and it was treated with activated carbon at 25 °C. The solution was then evaporated to approx. 70 ml and the pH adjusted to 7.0 with acetic acid. After cooling to 5 °C, the resulting product was filtered off, washed with water and dried. Thereby 8.0 g (77%) of the title compound was isolated as a white powder, m.p. 178-180 °C (dec.). HPLC indicated >96% purity.
I- T( 2- hydroksyetoksy) metyl]- 5-( tiokarbamovl) amino- lH- imidazol-4- karboksamid I-T(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide
Acetylklorid (1,6 g, 21 mM) ble tilsatt dråpevis under N2 til en oppløsning av ammoniumtiocyanat (1,6 g, 21 mM) i aceton (30 ml) ved 25 °C i løpet av 5 min. Etter koking under tilbakeløpskjøling i 15 min ble det avkjølt til 20 °C, og det dannede ammoniumklorid ble frafiltrert og vasket med aceton (10 ml). Acetyl chloride (1.6 g, 21 mM) was added dropwise under N 2 to a solution of ammonium thiocyanate (1.6 g, 21 mM) in acetone (30 mL) at 25 °C over 5 min. After boiling under reflux for 15 min, it was cooled to 20 °C, and the ammonium chloride formed was filtered off and washed with acetone (10 ml).
Til filtratet ble det tilsatt 5-amino-l-[[2-(acetyl-oksy)etoksy]metyl]-lH-imidazol-4-karboksamid (4,8 g, 20 mM). Blandingen ble kokt under tilbakeløpskjøling under N2 i 20 timer. Så ble metanol (40 ml) og kaliumkarbonat (5,8 g, 42 mM) oppløst i vann (12 ml) tilsatt, og blandingen ble kokt under tilbakeløpskjøling i 7 timer under N2. Vann (50 ml) ble tilsatt til hydrolyseblandingen, og den ble behandlet med aktivkull ved 25 °C. Oppløsningen ble så inndampet til ca. 30 ml og pH-verdien regulert til 7,0 med eddiksyre. Etter av-kjøling til 5 °C ble det dannede produkt frafiltrert, vasket med vann og tørket. Herved ble det isolert 3,2 g (62 %) av tittelforbindelsen som et hvitt pulver, sm.p. 175-177 °C (dek.). HPLC indikerte >94 % renhet. To the filtrate was added 5-amino-1-[[2-(acetyl-oxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (4.8 g, 20 mM). The mixture was refluxed under N2 for 20 hours. Then methanol (40 mL) and potassium carbonate (5.8 g, 42 mM) dissolved in water (12 mL) were added and the mixture was refluxed for 7 h under N 2 . Water (50 mL) was added to the hydrolysis mixture and it was treated with activated carbon at 25 °C. The solution was then evaporated to approx. 30 ml and the pH adjusted to 7.0 with acetic acid. After cooling to 5 °C, the product formed was filtered off, washed with water and dried. Thereby 3.2 g (62%) of the title compound was isolated as a white powder, m.p. 175-177 °C (dec.). HPLC indicated >94% purity.
l- metyl- 5-( tiokarbamovl) amino- lH- imidazol- 4- karboksamid 1-methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide
5-(N'-benzoyltiokarbamoyl)amino-1-metyl-1H-imidazol-4-karboksamid ble tilsatt til en blanding av aceton og metanol (1:1) (200 ml). Kaliumkarbonat (2,8 g, 20 mM) oppløst i vann (12 ml) ble tilsatt. Reaksjonsblandingen ble kokt under til-bakeløpskjøling under N2 i 6 timer, hvoretter eddiksyre (2,9 g, 48 mM) ble tilsatt. Etter omrøring i et isbad ble produktet frafiltrert, vasket og tørket. Derved ble det isolert 7,7 g (96 %) av tittelforbindelsen som et hvitt pulver, sm.p. 270-274 °C (dek.) (omdannelsen begynner ved ca. 220 °C). 5-(N'-benzoylthiocarbamoyl)amino-1-methyl-1H-imidazole-4-carboxamide was added to a mixture of acetone and methanol (1:1) (200 mL). Potassium carbonate (2.8 g, 20 mM) dissolved in water (12 mL) was added. The reaction mixture was refluxed under N 2 for 6 h, after which acetic acid (2.9 g, 48 mM) was added. After stirring in an ice bath, the product was filtered off, washed and dried. Thereby 7.7 g (96%) of the title compound was isolated as a white powder, m.p. 270-274 °C (dec.) (the conversion begins at about 220 °C).
En prøve utkrystallisert fra vann smelter ved 280-283 °C (dek.) (omdannelsen begynner ved ca. 220 °C). <13>C-NMR (DMSO-d6) 6 ppm: 184,0; 163,9; 134,8; 130,2; 127,3; 30,9. A sample crystallized from water melts at 280-283 °C (dec.) (the conversion begins at about 220 °C). <13>C-NMR (DMSO-d6) 6 ppm: 184.0; 163.9; 134.8; 130.2; 127.3; 30.9.
Beregnet for C6H9N50S: Calculated for C6H9N50S:
C 36,17 %, H 4,55 %, N 35,16 % C 36.17%, H 4.55%, N 35.16%
Funnet: C 36,06 %, H 4,53 %, N 35,05 %. l- etyl- 5-( tiokarbamoyl) amino- lH- imidazol- 4- karboksamid ble fremstilt på en lignende måte fra 5-(N'-benzoyltiokarbamoyl)-amino-l-etyl-lH-imidazol-4-karboksamid, sm.p. 265-268 °C (dek.). <13>C-NMR (DMS0-d6) 6 ppm: 183,8; 163,9; 133,8; 129,1; 127,8; 39,0; 15,2. Found: C 36.06%, H 4.53%, N 35.05%. 1-ethyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-(N'-benzoylthiocarbamoyl)amino-1-ethyl-1H-imidazole-4-carboxamide, m.p. p. 265-268 °C (dec.). <13>C-NMR (DMS0-d6) 6 ppm: 183.8; 163.9; 133.8; 129.1; 127.8; 39.0; 15.2.
Beregnet for CjH^NgOS: Calculated for CjH^NgOS:
C 39,42 %, H 5,20 %, N 32,84 % Funnet: C 39,37 %, H 5,19 %, N 32,71 %. C 39.42%, H 5.20%, N 32.84% Found: C 39.37%, H 5.19%, N 32.71%.
1-( 1- propyl)- 5-( tiokarbamovl) amino- lH- imidazol- 4- karboksamid ble fremstilt på en lignende måte fra 5-(N'-benzoyltiokarbamoyl )amino-l-(1-propyl)-lH-imidazol-4-karboksamid, sm.p. 197-198 °C (dek.). <13>C-NMR (DMSO-d6) 6 ppm: 183,8; 163,9; 134,4; 129,2; 127,7; 45,7; 22,7; 10,8. 1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-(N'-benzoylthiocarbamoyl)amino-1-(1-propyl)-1H-imidazole -4-carboxamide, m.p. 197-198 °C (dec.). <13>C-NMR (DMSO-d6) 6 ppm: 183.8; 163.9; 134.4; 129.2; 127.7; 45.7; 22.7; 10.8.
Beregnet for C8H13N50S: Calculated for C8H13N50S:
C 42,27 %, H 5,77 %, N 30,81 % C 42.27%, H 5.77%, N 30.81%
Funnet: C 42,16 %, H 5,84 %, N 30,86 %. l- benzyl- 5-( tiokarbamoyl) amino- lH- imidazol- 4- karboksamid ble fremstilt på en lignende måte fra 5-(N'-benzoyltiokarbamoyl)-amino-l-benzyl-lH-imidazol-4-karboksamid, sm.p. 264-266 °C (dek.) (omdannelsen begynner ved ca. 205 °C). <13>C-NMR (DMS0-d6) 6 ppm: 183,8; 163,9; 136,5; 134,5; 129,6; 128,6; 127,7; 127,4; 47,6. Found: C 42.16%, H 5.84%, N 30.86%. 1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-(N'-benzoylthiocarbamoyl)amino-1-benzyl-1H-imidazole-4-carboxamide, m.p. p. 264-266 °C (dec.) (conversion begins at about 205 °C). <13>C-NMR (DMS0-d6) 6 ppm: 183.8; 163.9; 136.5; 134.5; 129.6; 128.6; 127.7; 127.4; 47.6.
Beregnet for C12H13N50S: Calculated for C12H13N50S:
C 52,34 %, H 4,76 %, N 25,44 % C 52.34%, H 4.76%, N 25.44%
Funnet: C 52,31 %, H 4,73 %, N 25,52 %. Found: C 52.31%, H 4.73%, N 25.52%.
De følgende eksempler illustrerer fremgangsmåten ifølge oppfinnelsen. Eksemplene 1-7 illustrerer fremgangs-måtevariant a), og eksemplene 8-12 illustrerer fremgangs-måtevariant b). The following examples illustrate the method according to the invention. Examples 1-7 illustrate process variant a), and examples 8-12 illustrate process variant b).
Eksempel 1 Example 1
9- metylquanin 9- methylguanine
1-metyl-5-(tiokarbamoyl)amino-lH-imidazol-4-karboksamid (3,98 g, 20 mM) ble oppløst i 1 N natriumhydroksid (160 ml). Kobberacetat, H20 (4,6 g, 23 mM) ble tilsatt, og reaksjonsblandingen ble så kokt under tilbakeløpskjøling i 1 time. Etter avkjøling til 50 °C ble det dannede kobbersulfid frafiltrert. Filtratet ble surgjort med eddiksyre til pH 5,0. Det resulterende produkt ble frafiltrert ved 25 °C, vasket med vann og tørket. Herved ble det isolert 3,16 g (96 %) av tittelforbindelsen som et hvitt pulver, sm.p. >300 °C. <13>C-NMR (1 N NaOD) 6 ppm: 170,7; 163,6; 154,0; 141,4; 120,0; 32,2. 1-Methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (3.98 g, 20 mM) was dissolved in 1 N sodium hydroxide (160 mL). Copper acetate, H 2 O (4.6 g, 23 mM) was added and the reaction mixture was then refluxed for 1 hour. After cooling to 50 °C, the formed copper sulphide was filtered off. The filtrate was acidified with acetic acid to pH 5.0. The resulting product was filtered off at 25°C, washed with water and dried. Thereby 3.16 g (96%) of the title compound was isolated as a white powder, m.p. >300 °C. <13>C-NMR (1 N NaOD) 6 ppm: 170.7; 163.6; 154.0; 141.4; 120.0; 32.2.
Beregnet for C6H7N50: Calculated for C6H7N50:
C 43,63 %, H 4,27 %, N 42,41 % C 43.63%, H 4.27%, N 42.41%
Funnet: C 43,05 %, H 4,20 %, N 41,95 %. Found: C 43.05%, H 4.20%, N 41.95%.
Eksempel 2 Example 2
9- etylquanin 9- ethylquanine
9-etylguanin ble fremstilt på en lignende måte fra 1-etyl-5-(tiokarbamoyl)amino-lH-imidazol-4-karboksamid, sm.p. 9-Ethylguanine was prepared in a similar manner from 1-ethyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, m.p.
>300 °C. >300 °C.
Beregnet for C7H9N50, 1/4 H20: Calculated for C7H9N50, 1/4 H20:
C 45,77 %, H 5,21 %, N 38,13 % C 45.77%, H 5.21%, N 38.13%
Funnet: C 45,52 %, H 5,00 %, N 38,04 %. Found: C 45.52%, H 5.00%, N 38.04%.
Eksempel 3 Example 3
9-( 1- propyl) quanin 9-(1-propyl)quanine
9-(1-propyl)guanin ble fremstilt på en lignende måte fra l-(1-propyl)-5-(tiokarbamoyl)amino-lH-imidazol-4-karboksamid, sm.p. >300 °C. <13>C-NMR (DMS0-d6) 6 <pp>m: 156,8; 153,3; 151,0; 137,4; 116,5; 44,2;,22,7; 10,8. 9-(1-propyl)guanine was prepared in a similar manner from 1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, m.p. >300 °C. <13>C-NMR (DMS0-d6) 6 <pp>m: 156.8; 153.3; 151.0; 137.4; 116.5; 44.2;,22.7; 10.8.
Beregnet for C8HuN50: Calculated for C8HuN50:
C 49,73 %, H 5,74 %, N 36,25 % C 49.73%, H 5.74%, N 36.25%
Funnet: C 49,50 %, H 5,76 %, N 36,30 %. Found: C 49.50%, H 5.76%, N 36.30%.
Eksempel 4 Example 4
9- benzylguanin 9- benzylguanine
9-benzylguanin ble fremstilt på en lignende måte fra 1-benzyl-5-(tiokarbamoyl)amino-1H-imidazol-4-karboksamid, sm.p. >305-308 °C. <13>C-NMR (DMS0-d6) 6 ppm: 157,0; 153,8; 151,2; 137,6; 137,3; 128,7; 127,6; 127,2; 116,6; 45,9. 9-Benzylguanine was prepared in a similar manner from 1-benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, m.p. >305-308 °C. <13>C-NMR (DMS0-d6) 6 ppm: 157.0; 153.8; 151.2; 137.6; 137.3; 128.7; 127.6; 127.2; 116.6; 45.9.
Beregnet for C12H1:LN50<:>Calculated for C12H1:LN50<:>
C 59,74 %, H 4,59 %, N 29,03 % C 59.74%, H 4.59%, N 29.03%
Funnet: C 59,50 %, H 4,51 %, N 28,91 %. Found: C 59.50%, H 4.51%, N 28.91%.
Eksempel 5a Example 5a
9- f( 2- hvdroksyetoksy) metyl1quanin ( acyklovir) 9-f(2-hydroxyethoxy)methyl-1quanine (acyclovir)
1-[(2-hydroksyetoksy)metyl]-5-(tiokarbamoyl)amino-1H-imidazol-4-karboksamid (10,0 g, 38,6 mM) ble tilsatt til en suspensjon av kobbersulfat (7,0 g, 44 mM) i 6 N natriumhydroksid (80 ml) og ble omrørt ved værelsestemperatur i 4 timer. HPLC indikerte 100 % utbytte. Etter filtrering ble 50 % vandig eddiksyre (80, ml) tilsatt til filtratet. Etter en kort tid med koking under tilbakeløpskjøling ble materialet avkjølt til 5 °C. Produktet ble frafiltrert og utkrystallisert fra vann, idet behandling ble gjort med aktivkull. Herved ble det isolert 7,8 g (85 %) 9-[(2-hydroksyetoksy)metyl]guanin, 3/4 H20 (acyklovir) som et hvitt pulver. HPLC indikerte >99 % renhet, sm.p. ca. 250 °C (dek.). <13>C-NMR (DMS0-d6) 6 ppm: 156,8; 153,8; 151,4; 137,8; 116,5; 72,1; 70,4 og 59,9. 1-[(2-hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (10.0 g, 38.6 mM) was added to a suspension of copper sulfate (7.0 g, 44 mM) in 6 N sodium hydroxide (80 mL) and was stirred at room temperature for 4 hours. HPLC indicated 100% yield. After filtration, 50% aqueous acetic acid (80.ml) was added to the filtrate. After a short time of boiling under reflux, the material was cooled to 5 °C. The product was filtered off and crystallized from water, treatment being carried out with activated charcoal. Hereby 7.8 g (85%) of 9-[(2-hydroxyethoxy)methyl]guanine, 3/4 H 2 O (acyclovir) was isolated as a white powder. HPLC indicated >99% purity, m.p. about. 250 °C (dec.). <13>C-NMR (DMS0-d6) 6 ppm: 156.8; 153.8; 151.4; 137.8; 116.5; 72.1; 70.4 and 59.9.
Beregnet for C8HuN503, 3/4 H20: Calculated for C8HuN503, 3/4 H2O:
C 40,25 %, H 5,28 %, N 29,34 % C 40.25%, H 5.28%, N 29.34%
Funnet: C 40,39 %, H 5,22 %, N 29,37 %. Found: C 40.39%, H 5.22%, N 29.37%.
Eksempel 5b Example 5b
9- T( 2- hvdroksyetoksv) metyllquanin ( acyklovir) 9- T(2-hydroxyethoxy)methylquanine (acyclovir)
1-[(2-hydroksyetoksy)metyl]-5-(tiokarbamoyl)amino-1H-imidazol-4-karboksamid (1,30 g, 5,0 mM) ble tilsatt til en suspensjon av kobberacetat, H20 (1,15 g, .5,75 mM) i 1 N natriumhydroksid (60 ml), og det ble kokt under tilbakeløps-kjøling i 30 min. HPLC indikerte 100 % utbytte. Etter filtrering ble eddiksyre (5 ml) tilsatt til filtratet, og så ble To a suspension of copper acetate, H 2 O (1.15 g , .5.75 mM) in 1 N sodium hydroxide (60 ml) and refluxed for 30 min. HPLC indicated 100% yield. After filtration, acetic acid (5 mL) was added to the filtrate, and
oppvarming med aktivkull utført. Kullet ble frafiltrert, hvoretter materialet ble avkjølt til 5 °C. Det utfelte produkt ble frafiltrert, vasket med vann og tørket. Herved ble det isolert 0,92 g (77 %) 9-[(2-hydroksyetoksy)metyl]guanin, 3/4 H20 som et hvitt pulver. HPLC indikerte >99 % renhet. heating with activated carbon carried out. The coal was filtered off, after which the material was cooled to 5 °C. The precipitated product was filtered off, washed with water and dried. This isolated 0.92 g (77%) of 9-[(2-hydroxyethoxy)methyl]guanine, 3/4 H 2 O as a white powder. HPLC indicated >99% purity.
Anvendelsen av andre tungmetallsalter og varierende mengder natriumhydroksid i fremgangsmåten ifølge eksempel 5 er vist i den følgende tabell. The use of other heavy metal salts and varying amounts of sodium hydroxide in the method according to example 5 is shown in the following table.
Eksempel 6 Example 6
9- f 1, 3- dihydroksy-( 2- propyloksy) metyllquanin 9- f 1, 3- dihydroxy-(2- propyloxy) methylquanine
1-[1,3-dihydroksy-(2-propyloksy)metyl]-5-(tiokarbamoyl )amino-lH-imidazol-4-karboksamid (0,58 g, 2,0 mM) ble tilsatt til en suspensjon av kobbersulfat (0,32 g, 2,3 mM) i 3 N natriumhydroksid (8 ml), og det ble kokt under tilbakeløps-kjøling i 1 time. HPLC indikerte 100 % utbytte. Etter filtrering ble 33 % vandig eddiksyre (6 ml) tilsatt til filtratet, og det ble kokt under tilbakeløpskjøling på nytt mens det ble behandlet med aktivkull. Kullet ble frafiltrert, og oppløs-ningen ble avkjølt til 5 °C. Filtrering, vasking med vann og tørking resulterte i 0,33 g (61 %) 9-[1,3-dihydroksy-(2-propyloksy)metyl]guanin, 3/4 H20 som et hvitt pulver, sm.p. ca. 245 °C (dek.). <13>C-NMR (DMS0-d6) 6 ppm: 157,0; 153,9; 151,3; 137,6; 116,3; 79,9; 71,4; 60,8. To a suspension of copper sulfate ( 0.32 g, 2.3 mM) in 3 N sodium hydroxide (8 mL) and refluxed for 1 h. HPLC indicated 100% yield. After filtration, 33% aqueous acetic acid (6 mL) was added to the filtrate and refluxed again while treating with activated carbon. The charcoal was filtered off, and the solution was cooled to 5 °C. Filtration, washing with water and drying yielded 0.33 g (61%) of 9-[1,3-dihydroxy-(2-propyloxy)methyl]guanine, 3/4 H 2 O as a white powder, m.p. about. 245 °C (dec.). <13>C-NMR (DMS0-d6) 6 ppm: 157.0; 153.9; 151.3; 137.6; 116.3; 79.9; 71.4; 60.8.
Beregnet for C9H13N504, 3/4 H20: Calculated for C9H13N504, 3/4 H20:
C 40,22 %, H 5,43 %, N 26,06 % C 40.22%, H 5.43%, N 26.06%
Funnet: C 40,25 %, H 5,31 %, N 25,58 %. Found: C 40.25%, H 5.31%, N 25.58%.
Eksempel 7 Example 7
9- p- D- ribofuranosylquanin ( quanosin) 9-p-D-ribofuranosylquanine (guanosine)
5-amino-l- ((3-D-ribof uranosyl) -lH-imidazol-4-karboksamid (5,0 g, 19,4 mM) og benzoylisotiocyanat (3,3 g, 20 mM) ble omrørt ved værelsestemperatur i DMF (40 ml) i 1 time. Opp-løsningsmidlet ble strippet av i vannstrålevakuum. Resten ble 5-Amino-1-((3-D-ribophuranosyl)-1H-imidazole-4-carboxamide (5.0 g, 19.4 mM) and benzoyl isothiocyanate (3.3 g, 20 mM) were stirred at room temperature in DMF (40 mL) for 1 h. The solvent was stripped off in water jet vacuum. The residue was
oppløst i metanol (160 ml), og kaliumkarbonat (1,6 g, 11,6 mM) i vann (8 ml) ble tilsatt, hvoretter blandingen ble kokt under tilbakeløpskjøling i 2 timer. Etter avkjøling til værelsestemperatur ble eddiksyre tilsatt inntil pH 6. Reaksjonsblandingen ble inndampet i vannstrålevakuum, og resten ble krystallisert fra etanol. Herved ble det isolert 5,0 g urent l-(p-D-ribofuranosyl)-5-(tiokarbamoyl)amino-lH-imidazol-4-karboksamid. HPLC indikerte en renhet på ca. 65 % (de gjenværende 35 % var hovedsakelig kaliumacetat). dissolved in methanol (160 mL), and potassium carbonate (1.6 g, 11.6 mM) in water (8 mL) were added, after which the mixture was refluxed for 2 hours. After cooling to room temperature, acetic acid was added until pH 6. The reaction mixture was evaporated in a water jet vacuum, and the residue was crystallized from ethanol. 5.0 g of impure 1-(β-D-ribofuranosyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide were thereby isolated. HPLC indicated a purity of approx. 65% (the remaining 35% was mainly potassium acetate).
Det urene produkt av 1-(p-D-ribofuranosyl)-5-(tiokarbamoyl )amino-lH-imidazol-4-karboksamid (5,0 g) ble tilsatt til en suspensjon av kobbersulfat (2,9 g, 18 mM) i 3 N natriumhydroksid (60 ml), og det ble kokt under tilbakeløps-kjøling i 1 time. Etter filtrering ble 33 % vandig eddiksyre The crude product of 1-(β-D-ribofuranosyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (5.0 g) was added to a suspension of copper sulfate (2.9 g, 18 mM) in 3 N sodium hydroxide (60 ml) and refluxed for 1 hour. After filtration, 33% became aqueous acetic acid
(30 ml) tilsatt til filtratet, og det ble kokt under tilbake-løpskjøling på nytt mens det ble behandlet med aktivkull. Kullet ble frafiltrert, og oppløsningen ble avkjølt til værelsestemperatur over natten. Filtrering, vasking med vann og tørking gav 2,0 g (65 %) 9-p-D-ribofuranosylguanin, H20 (guanosin-H20) som et hvitt pulver, sm.p. 250 °C (dek.). Produktet hadde de samme fysikalske data som en autentisk prøve av guanosin- H20. (30 mL) was added to the filtrate and refluxed again while treating with activated charcoal. The carbon was filtered off, and the solution was cooled to room temperature overnight. Filtration, washing with water and drying gave 2.0 g (65%) of 9-p-D-ribofuranosylguanine, H 2 O (guanosine-H 2 O) as a white powder, m.p. 250 °C (dec.). The product had the same physical data as an authentic sample of guanosine-H20.
Eksempel 8 Example 8
9-( 1- propyl) quanin l-(1-propyl)-5-(tiokarbamoyl)amino-lH-imidazol-4-karboksamid (1,14 g, 5,0 mM) og natriumwolframat (0,2 g) ble oppløst i 1 N natriumhydroksid (50 ml) ved 0 °C. 35 % hydrogenperoksid (1,8 ml, 20 mM) i vann (5 ml) ble dråpevis tilsatt ved 0-10 °C i løpet av 30 min. Etter omrøring i et isbad i 1 time ble pH regulert til 5 med eddiksyre. Det dannede produkt ble frafiltrert, vasket med vann og tørket. Herved ble det isolert 0,41 g (42 %) av tittelforbindelsen som et hvitt pulver : HPLC indikerte > 98 % renhet. Produktet hadde de samme fysikalske data som produktet ifølge eksempel 3. 9-(1-propyl)guanine 1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (1.14 g, 5.0 mM) and sodium tungstate (0.2 g) were dissolved in 1 N sodium hydroxide (50 ml) at 0 °C. 35% hydrogen peroxide (1.8 mL, 20 mM) in water (5 mL) was added dropwise at 0-10 °C over 30 min. After stirring in an ice bath for 1 hour, the pH was adjusted to 5 with acetic acid. The product formed was filtered off, washed with water and dried. Hereby 0.41 g (42%) of the title compound was isolated as a white powder: HPLC indicated >98% purity. The product had the same physical data as the product according to example 3.
Eksempel 9 Example 9
9- benzylquanin l-benzyl-5-(tiokarbamoyl)amino-lH-imidazol-4-karboks-. amid (2,75 g, 10,0 mM) og natriumwolframat (0,1 g) ble opp-slemmet i 6 N natriumhydroksid (20 ml) ved 5 °C. 35 % hydrogenperoksid (4,0 ml, 44 mM) ble dråpevis tilsatt ved 5-15 °C i løpet av 30 min. Vann (60 ml) ble tilsatt til den resulterende reaksjonsblanding. Etter omrøring i 1 time i et isbad ble pH regulert til 5 med saltsyre. Det dannede produkt ble frafiltrert, vasket med vann og tørket. Herved ble det isolert 1,30 g (54 %) av tittelforbindelsen som et hvitt pulver. HPLC indikerte ca. 98 % renhet. Produktet hadde de samme fysikalske data som produktet ifølge eksempel 4. 9- benzylquanine 1-benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carbox-. amide (2.75 g, 10.0 mM) and sodium tungstate (0.1 g) were slurried in 6 N sodium hydroxide (20 mL) at 5 °C. 35% hydrogen peroxide (4.0 mL, 44 mM) was added dropwise at 5-15°C over 30 min. Water (60 mL) was added to the resulting reaction mixture. After stirring for 1 hour in an ice bath, the pH was adjusted to 5 with hydrochloric acid. The product formed was filtered off, washed with water and dried. Thereby 1.30 g (54%) of the title compound was isolated as a white powder. HPLC indicated approx. 98% purity. The product had the same physical data as the product according to example 4.
Eksempel 10 Example 10
9- metylquanin 9- methylguanine
9-metylguanin ble fremstilt på en lignende måte fra 1 -metyl-5- (tiokarbamoyl )amino-lH-imidazol-4-karboksamid. Produktet hadde de samme fysikalske data som produktet ifølge eksempel 1. 9-Methylguanine was prepared in a similar manner from 1-methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide. The product had the same physical data as the product according to example 1.
Eksempel 11 Example 11
9- etylquanin 9- ethylquanine
9-etylguanin ble fremstilt på en lignende måte fra 1-etyl-5-(tiokarbamoyl)amino-lH-imidazol-4-karboksamid. Produktet hadde de samme fysikalske data som produktet ifølge eksempel 2. 9-Ethylguanine was prepared in a similar manner from 1-ethyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide. The product had the same physical data as the product according to example 2.
Eksempel 12 Example 12
9- r( 2- hydroksyetoksy) mety11quanin ( acyklovir) 9-r(2-hydroxyethoxy)methy11quanine (acyclovir)
1-[(2-hydroksyetoksy)metyl]-5-(tiokarbamoyl)amino-1H-imidazol-4-karboksamid (2,59 g, 10,0 mM) og natriumwolframat (0,05 g) ble oppløst i 6 N natriumhydroksid (20 ml) ved 5 °C. 35 % hydrogenperoksid (4,0 ml, 44 mM) ble dråpevis tilsatt ved 5-15 °C i løpet av 15 min. Etter omrøring i 15 min ved 0-5 °C indikerte HPLC 59 % utbytte av tittelforbindelsen. pH-verdien i reaksjonsblandingen ble regulert til 5,5 med 25 % vandig eddiksyre. Det resulterende produkt ble frafiltrert, vasket med vann og tørket, noe som gav 1,13 g (50 %) av tittelforbindelsen som et hvitt pulver. HPLC indikerte en renhet på ca. 97 %. Produktet hadde de samme fysikalske data som produktet ifølge eksempel 5. 1-[(2-hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (2.59 g, 10.0 mM) and sodium tungstate (0.05 g) were dissolved in 6 N sodium hydroxide (20 mL) at 5 °C. 35% hydrogen peroxide (4.0 mL, 44 mM) was added dropwise at 5-15 °C over 15 min. After stirring for 15 min at 0-5 °C, HPLC indicated 59% yield of the title compound. The pH value in the reaction mixture was adjusted to 5.5 with 25% aqueous acetic acid. The resulting product was filtered off, washed with water and dried to give 1.13 g (50%) of the title compound as a white powder. HPLC indicated a purity of approx. 97%. The product had the same physical data as the product according to example 5.
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DK135489A DK135489D0 (en) | 1989-03-20 | 1989-03-20 | PROCEDURE FOR THE PREPARATION OF 9-SUBSTITUTED GUANINE DERIVATIVES AND INTERMEDIATES FOR USING THE PROCEDURE |
PCT/DK1990/000077 WO1990011283A1 (en) | 1989-03-20 | 1990-03-19 | A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process |
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IT1264599B1 (en) * | 1993-06-14 | 1996-10-04 | Solar Chem Sa | PROCESS FOR THE SYNTHESIS OF 9- (2-IDROSSIETOSSIMETIL) - GUANINA |
GB9520364D0 (en) * | 1995-10-05 | 1995-12-06 | Chiroscience Ltd | Compouundds |
US6761758B2 (en) | 2002-09-04 | 2004-07-13 | Xerox Corporation | Alkylated tetrakis(triaminotriazine) compounds and phase change inks containing same |
US6860928B2 (en) | 2002-09-04 | 2005-03-01 | Xerox Corporation | Alkylated urea and triaminotriazine compounds and phase change inks containing same |
US6811595B2 (en) | 2002-09-04 | 2004-11-02 | Xerox Corporation | Guanidinopyrimidinone compounds and phase change inks containing same |
US6872243B2 (en) | 2002-09-04 | 2005-03-29 | Xerox Corporation | Phase change inks containing gelator additives |
US7220300B2 (en) | 2004-12-04 | 2007-05-22 | Xerox Corporation | Phase change inks containing bis(urea-urethane) compounds |
US7153349B2 (en) | 2004-12-04 | 2006-12-26 | Xerox Corporation | Phase change inks containing curable trans-1,2-cyclohexane bis(urea-urethane) compounds |
US7144450B2 (en) | 2004-12-04 | 2006-12-05 | Xerox Corporation | Phase change inks containing trans-1,2-cyclohexane bis(urea-urethane) compounds |
US7317122B2 (en) | 2004-12-04 | 2008-01-08 | Xerox Corporation | Curable trans-1,2-cyclohexane bis(urea-urethane) compounds |
US7560587B2 (en) | 2004-12-04 | 2009-07-14 | Xerox Corporation | Bis[urea-urethane] compounds |
US7314949B2 (en) | 2004-12-04 | 2008-01-01 | Xerox Corporation | Trans-1,2-cyclohexane bis(urea-urethane) compounds |
EP3062949B2 (en) | 2013-10-29 | 2023-05-24 | SWEP International AB | A method of brazing a plate heat exchanger using scren printed brazing material |
CN115504977B (en) * | 2022-09-23 | 2024-02-09 | 海南锦瑞制药有限公司 | Preparation method of ganciclovir and preparation method of ganciclovir for injection |
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US4451478A (en) * | 1982-03-12 | 1984-05-29 | Newport Pharmaceuticals International, Inc. | Imidazole compounds |
US4602089A (en) * | 1982-03-12 | 1986-07-22 | Newport Pharmaceuticals, Inc. | Process for preparing purine compounds |
JPS6055071B2 (en) * | 1982-04-16 | 1985-12-03 | 四国化成工業株式会社 | Imidazolyl succinic acid compound and epoxy resin curing method using the compound |
HUT36464A (en) * | 1983-05-24 | 1985-09-30 | Newport Pharmaceuticals | Process for producing erythro-4-amino-3-/2-hydroxy-3-alkyl/-imidazol-5-carboxamide |
EP0219838A3 (en) * | 1985-10-22 | 1988-04-06 | Takeda Chemical Industries, Ltd. | Carbocyclic purine nucleosides, their production and use |
MY101126A (en) * | 1985-12-13 | 1991-07-31 | Beecham Group Plc | Novel compounds |
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1989
- 1989-03-20 DK DK135489A patent/DK135489D0/en not_active Application Discontinuation
-
1990
- 1990-03-16 IE IE99490A patent/IE62042B1/en unknown
- 1990-03-19 BR BR909007230A patent/BR9007230A/en not_active Application Discontinuation
- 1990-03-19 ES ES90905442T patent/ES2061023T3/en not_active Expired - Lifetime
- 1990-03-19 DE DE69013146T patent/DE69013146T2/en not_active Expired - Fee Related
- 1990-03-19 EP EP90905442A patent/EP0464112B1/en not_active Expired - Lifetime
- 1990-03-19 RU RU9093004872A patent/RU2090566C1/en active
- 1990-03-19 CA CA002047217A patent/CA2047217A1/en not_active Abandoned
- 1990-03-19 WO PCT/DK1990/000077 patent/WO1990011283A1/en active IP Right Grant
- 1990-03-19 HU HU902874A patent/HU206715B/en not_active IP Right Cessation
- 1990-03-19 DK DK90905442.1T patent/DK0464112T3/en active
- 1990-03-19 US US07/761,890 patent/US5223619A/en not_active Expired - Fee Related
- 1990-03-19 RO RO148411A patent/RO109737B1/en unknown
- 1990-03-19 KR KR1019910701187A patent/KR0142098B1/en not_active IP Right Cessation
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- 1990-03-20 AR AR90316421A patent/AR245719A1/en active
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- 1990-03-20 DD DD90338906A patent/DD293116A5/en not_active IP Right Cessation
- 1990-03-20 GR GR900100212A patent/GR1001096B/en unknown
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1991
- 1991-09-19 FI FI914418A patent/FI97387C/en active
- 1991-09-19 RU SU915001705A patent/RU2042668C1/en active
- 1991-09-19 NO NO913686A patent/NO178497C/en unknown
- 1991-09-20 BG BG95145A patent/BG60590B1/en unknown
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1992
- 1992-10-02 HR HRP-545/90A patent/HRP920907B1/en not_active IP Right Cessation
- 1992-12-02 LV LVP-92-250A patent/LV10455B/en unknown
-
1993
- 1993-01-27 LT LTIP297A patent/LT3183B/en not_active IP Right Cessation
- 1993-08-25 GE GEAP19931494A patent/GEP19971014B/en unknown
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